DESCRIPTION: The monoamines, including dopamine and serotonin, play important roles in the regulation of behavior in all animals. They act by complex modulatory mechanisms to change the intrinsic firing properties of neurons and the strength of synaptic connections. These changes occur within the context of neural networks that coordinate behaviors, leading to adaptive changes in behavioral output. The overall goal of our laboratory is to show how these cellular mechanisms lead to behavioral plasticity by studying how dopamine, serotonin and octopamine reconfigure the 14-neuron pyloric network in the stomatogastric ganglion of the spiny lobster, Panulirus interruptus. This network generates a rhythmic motor pattern whose properties are determined by the neuromodulators that are present. We have shown that the monoamines can each evoke a unique variant of the pyloric rhythm by direct actions on each of the pyloric neurons and synapses. In this grant, we propose to extend our knowledge of the ionic mechanisms by which the amines reconfigure the pyloric network. We will study amine modulation of ionic currents that generate rhythmic bursting and bistable plateau potential activity, using voltage clamp and multiphoton microscopic calcium imaging. We will also determine whether amines modify synaptic transmission by affecting currents that are different from those modulated to alter firing properties. To better relate these molecular effects to normal neuronal firing, we will drive the neuron in voltage clamp with realistic waveforms that mimic the natural oscillations seen during the pyloric rhythm. In the intact animal, the pyloric network is simultaneously affected by multiple neuromodulators, and these may interact in non-linear ways; we will study this non-linear interaction, or metamodulation, with mixtures of neuromodulators. This work will yield new insights into the detailed mechanisms by which a set of neuromodulators reconfigures a neural network. Because neuromodulatory compounds are conserved and membrane currents and synaptic transmission are similar in network neurons ranging from the pyloric circuit to human cortical networks, our results will suggest common principles for generating behavioral plasticity in vertebrates and invertebrates alike.